The goal of this proposal is to understand how the Beclin 1/vacuolar protein sorting-associated protein 34 (VPS34) complex contributes to breast cancer progression and to determine how to sensitize tumor cells that are deficient in Beclin 1/VPS34 function to drugs that promote tumor cell death. Breast cancer is the most commonly diagnosed cancer among women worldwide and the second leading cause of cancer related mortality. Despite the availability of targeted therapeutics, the overall survival rate for stage I metastatic disease remains 23%. Therefore, there is a need to develop novel approaches for the treatment of advanced stage breast cancer. The applicant hypothesizes that one such approach could exploit Beclin 1/VPS34 function in breast cancer progression. Beclin 1 is monoallelically deleted in 40% of human breast cancer and there is an inverse correlation between Beclin 1 expression and poor prognosis in ER negative subtypes of breast cancer. In addition, low Beclin 1 expression serves as an independent predictor of patient survival. Beclin 1 interacts with and activates VPS34, the mammalian Class III phosphatidylinositol, to regulate multiple membrane trafficking pathways including autophagy, growth factor receptor trafficking and cytokinesis. The individual contribution of each of these trafficking pathways to cancer is unknown and needs to be investigated to understand the impact of Beclin 1 loss on breast cancer progression. Previous studies in the applicant's lab have shown that loss of Beclin 1 expression is associated with a sustained increase in AKT and ERK signaling downstream of the IGF and EGF receptors. In addition, loss of Beclin 1 expression in breast carcinoma cells leads to increased invasion. These preliminary findings suggest that VPS34 inhibitors, which are currently in clinical trials, may negatively impact tumor treatment. The work that the applicant proposes here will explore how the Beclin 1/VPS34 complex contributes to breast cancer progression. The applicant hypothesizes that inhibiting the Beclin1/VPS34 complex will lead to the upregulation of specific pathways that promote tumor growth and progression and that targeting these pathways in tumors with low Beclin 1 expression or in combination with VPS34 inhibition will suppress tumor cell viability. The goal with this proposal is to dissect out the roe of each Beclin 1/VPS34 complex in breast cancer progression with respect to tumor growth, metastasis, and tumor metabolism both in vitro and in vivo (Aim 1). Furthermore, mechanisms that sensitize breast cancer cells to death upon Beclin 1/VPS34 inhibition will be identified as a means to target Beclin 1 deficient tumors and optimize VPS34 inhibitors as potential therapeutic agents (Aim 2). The studies in this proposal will enhance our understanding of the role of Beclin 1 in breast cancer and can give insight into novel therapies for advanced stage breast cancer disease.